Related Experiment Videos
Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy
B A Minassian1, R Aiyar, S Alic
1Division of Neurology, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Ontario, Canada. bminass@sickkids.ca
Background:
X-Linked myopathy with excessive autophagy (XMEA) is a childhood-onset slowly progressive disease of skeletal muscle with no cardiac, nervous system, or other organ involvement. Pathology is distinctive: membrane-bound autophagic vacuoles, multifold reduplication of the basement membrane, and intense deposition of membrane attack complex and calcium at the myofiber surface. XMEA has been linked to the most telomeric 10.5 cM of Xq28. The authors now report identification of new families, refinement of the locus, mapping of genes to the region, and screening of candidate genes for mutations.
Methods And Results:
Seven new families were ascertained, including an American family with XMEA. Using 11 new microsatellite genetic markers, the authors fine-mapped a recombination in this family and a common ancestral haplotype in two French families, which localized the gene in a 4.37-Mb region. Sequence data were assembled from public and private databases and a near-continuous sequence derived for the entire region. With this sequence, a gene map of 82 genes and 28 expressed sequence tag clusters was constructed; to date, 12 candidate genes have been screened for mutations.
Conclusions:
This study doubles the number of reported families with XMEA and more firmly establishes its distinctive clinicopathologic features. It also advances the search for the XMEA causative defect by reducing the disease locus to approximately half its previous size, assembling an almost complete sequence of the refined region, identifying all known genes in this sequence, and excluding the presence of mutations in 10% of these genes.
Insights
Researchers identified new families with X-linked myopathy with excessive autophagy (XMEA), a rare childhood muscle disease. They refined the disease gene location, aiding the search for causative mutations and understanding XMEA.
Area of Science:
- Genetics
- Neuromuscular Disorders
- Molecular Biology
Background:
- X-linked myopathy with excessive autophagy (XMEA) is a progressive childhood skeletal muscle disease.
- Distinctive pathology includes autophagic vacuoles and basement membrane abnormalities.
- Previous studies linked XMEA to the Xq28 region.
Purpose of the Study:
- Identify new families with XMEA.
- Refine the genetic locus for XMEA.
- Map genes within the refined region and screen candidate genes for mutations.
Main Methods:
- Ascertainment of seven new families with XMEA.
- Fine-mapping the disease locus using 11 microsatellite markers.
- Assembling sequence data and constructing a gene map of the refined region.
- Screening 12 candidate genes for mutations.
Main Results:
- The XMEA locus was refined to a 4.37-Mb region.
- A gene map of 82 genes and 28 EST clusters was created for the region.
- Mutations were excluded in 10% of the screened candidate genes.
Conclusions:
- This study doubles the number of reported XMEA families and confirms its unique features.
- The refined locus advances the search for the causative genetic defect in XMEA.
- The comprehensive gene map and screening provide a foundation for further investigation.